The invention relates to a novel method for producing substituted 3,3-diarylpropylamine derivatives. In particular, it relates to the production of such compounds by hydrocarbonylation/hydroformylation with subsequent reductive amination.
The abovementioned 3,3-diarylpropylamine derivatives are used in the treatment of urinary incontinence and other spasmogenic conditions (see WO 99/58478). The methods described there for producing the 3,3-diphenylpropylamine derivatives are for the most part multi-stage and for the production of optically active compounds require for the most part enantiomer separation.
The underlying object of the invention is, therefore, to provide new methods for the production of substituted 3,3-diarylpropylamine derivatives, that are simpler than the ones described in the state of the art, i.e. involve less stages, and that, apart from this, allow a stereo-selective synthesis of the target compounds.
The object of the invention is a method for producing 3,3-diarylpropylamines of the general formula I 
wherein
Ar represents a substituted or unsubstituted aryl radical,
X represents H, OH or OR3,
Y represents Cl, Br, I, CN, CHO, CH2OR, COOH, COOR, wherein R represents C1-C10-alkyl or a substituted or unsubstituted aryl radical, or C1-C10-alkyl,
R1, R2 represents C1-C10-alkyl or C3-C8-cycloalkyl, wherein R1 and R2 can be linked to form a cyclical structure,
and wherein R3 represents a radical, that is derived from one of the following compounds:
(i) the amino acids D-proline, L-proline, D-alanine, L-alanine, D-asparagine, L-asparagine, D-asparagine acid, L-asparagine acid, D-glutamine, L-glutamine, D-glutamine acid, L-glutamine acid, D-phenylalanine, L-phenylalanine, D-histidine, L-histidine, D-leucine, L-leucine, D-serine, L-serine, L-threonine, D-threonine, D-tryptophane, L-tryptophane, D-tyrosine, L-tyrosine, D-valine, L-valine, D-cysteine, L-cysteine, D-methionine, L-methionine, D-isoleucine, L-isoleucine, or the alcohols that are produced by these amino acids by reduction of the carboxylic acid function to the hydroxymethylene unit,
(ii) the amino acids N-diphenylphosphanyl-D-alanine, N-di-phenylphosphanyl-L-alanine, N-diphenylphosphanyl-D-proline, N-diphenylphosphanyl-L-proline, N-diphenylphosphanyl-D-phenylalanine, N-diphenylphosphanyl-L-phenylalanine, and the alcohols that are produced by these amino acids by reduction of the carboxylic acid function to the hydroxymethylene unit,
(iii) xcex1-hydroxycarboxylic acid derivatives of the general formula 
xe2x80x83respectively in the form of both optical antipodes, wherein R4 represents a linear or branched C1-C10-alkyl group or cycloalkyl group or a substituted or unsubstituted aryl radical and R5 represents C1-C10-alkyl, cycloalkyl, acyl, alkoxycarbonyl, benzoyl, diphenylphosphanyl, dicyclohexylphosphanyl or diarylphosphanyl,
(iv) the compounds of the general formula 
xe2x80x83wherein R6 represents a substituent selected from the group comprising PPh2, P(C6H11)2, P(aryl)2, alkyl, acyl, alkoxycarbonyl, benzoyl, arylcarbonyl, diarylphosphanyl and dicyclohexylphosphanyl, and their stereoisomers,
(v) the compounds of the general formula 
xe2x80x83wherein R7 represents a linear or branched C1-C10-alkyl group or a substituted or unsubstituted aryl radical, and stereoisomers of this,
(vi) the acids
xe2x80x83(R)-acetoxyphenylacetic acid,
xe2x80x83(R)- and (S)-1,4-benzodioxane-2-carboxylic acid,
xe2x80x83(R)-(xe2x88x92)- and (S)-(+)-hexahydro-acetoxymandelic acid,
xe2x80x83(2R, 3S)-2,3-O-isopropylidene-2,3-dihydroxybutyric acid and its stereoisomers,
xe2x80x83(+)- and (xe2x88x92)-menthyloxyacetic acid,
xe2x80x83(R)- and (S)-3-phenyl-2-acyloxypropionic acid,
xe2x80x83(R)- and (S)-acetoxymandelic acid,
xe2x80x83(R)- and (S)-xcex1-methoxy-xcex1-trifluoromethylphenylacetic acid,
xe2x80x83(S)-(+)-alpha-methoxyphenylacetic acid,
xe2x80x83(R)- and (S)-5-oxo-tetrahydrofurane-2-carboxylic acid,
xe2x80x83and the alcohols that are produced from these acids by reduction of the carboxylic acid function to the hydroxymethylene unit,
(vii) compounds of the general formula 
xe2x80x83wherein R8 represents a substituted or unsubstituted aryl radical and R9 a hydrogen or a linear or branched C1-C10-alkyl radical,
(viii) xcex1-naphthol, xcex2-naphthol or (R)- or (S)-1-(9-anthryl)-2,2,2-trifluoroethanol,
(ix) 2-methylamino-1-phenyl-propan-1-ol (ephedrine) in all stereomer forms,
or R3 represents one of the following radicals:
(x) phosphite radicals of the general formula xe2x80x94P(OR10) (OR11), wherein R10 and R11 can be the same or different and represent an if necessary polycyclic or bridged aryl radical,
(xi) C1-C10-alkyl, branched or linear,
(xii) acyl,
(xiii) benzyl or substituted benzyl radicals,
characterised in that compounds of the general formula (II) 
xe2x80x83wherein X, Y and Ar are as defined above, are transformed together with carbon monoxide (CO) and hydrogen (H2)in the presence of a transition metal catalyst and the resultant oxo compounds are allowed to react in the presence of a transition metal catalyst with an amine of the general formula HNR1R2, wherein R1 and R2 are as defined above.
In formula I, the substituent X represents hydrogen (H), hydroxy (OH) or the group OR3.
Here, the substituent R3 can have the meaning assigned to substituents R and Rxe2x80x2 in claim 1 of patent WO 99/58478.
R3 preferably represents a radical that is derived from the following compounds and alcohols:
(i) the amino acids D-proline, L-proline, D-alanine, L-alanine, D-asparagine, L-asparagine, D-asparagine acid, L-asparagine acid, D-glutamine, L-glutamine, D-glutamine acid, L-glutamine acid, D-phenylalanine, L-phenylalanine, D-histidine, L-histidine, D-leucine, L-leucine, D-serine, L-serine, L-threonine, D-threonine, D-tryptophane, L-tryptophane, D-tyrosine, L-tyrosine, D-valine, L-valine, D-cysteine, L-cysteine, D-methionine, L-methionine, D-isoleucine, L-isoleucine, or the alcohols that are produced by these amino acids by reduction of the carboxylic acid function to the hydroxymethylene unit.
xe2x80x83In these amino acid radicals, the bonding to the oxygen atom takes place according to the formula xe2x80x94Oxe2x80x94R3 via the OH group of the abovementioned amino acids, as shown in the following graphic formula: 
xe2x80x83bzw. = or
(ii) Furthermore, the substituent R3 can be derived from the following amino acid derivatives:
xe2x80x83the amino acids N-diphenylphosphanyl-D-alanine, N-diphenylphosphanyl-L-alanine, N-diphenylphosphanyl-D-proline, N-diphenylphosphanyl-L-proline, N-diphenylphosphanyl-D-phenylalanine, N-diphenylphosphanyl-L-phenylalanine, and the alcohols that are produced by these amino acids by reduction of the carboxylic acid function to the hydroxymethylene unit.
(iii) According to a further embodiment R3 can be derived from the following xcex1-hydroxycarboxylic acids:
xe2x80x83xcex1-hydroxycarboxylic acid derivatives of the general formula 
xe2x80x83respectively in the form of both optical antipodes, wherein R4 represents a linear or branched C1-C10-alkyl group or cycloalkyl group or a substituted or unsubstituted aryl radical and R5 represents C1-C10-alkyl, cycloalkyl, acyl, alkoxycarbonyl, benzoyl, diphenylphosphanyl, dicyclohexylphosphanyl or diarylphosphanyl.
xe2x80x83Preferred examples are (R)- and (S)-acetoxy-phenylacetic acid, (S)-(+)- and R-(xe2x88x92)-alphamethoxyphenylacetic acid, (R)- and (S)-3-phenyl-2-acyloxypropionic acid.
(iv) R3 can, furthermore, be derived from the carboxylic acids or alcohols shown below: 
xe2x80x83wherein R6 represents a substituent selected from the group comprising PPh2, alkyl, acyl, alkoxycarbonyl, benzoyl, arylcarbonyl, diphenylphosphanyl, diarylphosphanyl and dicyclohexylphosphanyl, and stereoisomers of these.
(v) Furthermore, R3 be derived from the carboxylic acids or alcohols shown below: 
xe2x80x83wherein R7 represents a linear or branched C1-C10-alkyl group or a substituted or unsubstituted aryl radical, and stereoisomers of this.
(vi) Furthermore, the substituent R3 can be derived from one of the carboxylic acids shown below:
1. (R)-acetoxyphenylacetic acid or the enantiomer 
2. (R)-1,4-benzodioxane-2-carboxylic acid or the enantiomer 
3. (R)-(xe2x88x92)-hexahydroacetoxymandelic acid or the enantiomer 
4. (2R, 3S)-2,3-O-isopropylidene-2,3-dihydroxy-butyric acid or the enantiomer 
5. (+)-menthyloxyacetic acid or the enantiomer 
6. (S)-(+)-alpha-menthoxyphenylacetic acid or the enantiomer 
7. (R)-5-oxo-tetrahydrofurane-2-carboxylic acid or the enantiomer 
8. (R)-3-phenyl-2-acyloxypropionic acid or the enantiomer 
xe2x80x83wherein R is as defined above.
9. (R)-xcex1-methoxy-xcex1-trifluoromethylphenylacetic acid or the enantiomer 
xe2x80x83All the abovementioned acids have one or more asymmetric centres and are used in an optically active manner.
xe2x80x83The bonding of the acids to the oxygen atom according to the formula xe2x80x94Oxe2x80x94R3 again takes place as in the other abovementioned carboxylic acids or alcohols via the OH group, so that generally esters or ethers with the following structure result: 
(vii) The radical R3 can, furthermore, be derived from compounds of the general formula 
xe2x80x83wherein R8 represents a substituted or unsubstituted aryl radical and R9 hydrogen or a linear or branched C1-C10-alkyl radical.
xe2x80x83Again, the bonding of the substituted R3 takes place via the oxygen atom, so that aryl ethers result.
(viii) The substituent R3 can, furthermore, be derived from xcex1-naphthol, xcex2-naphthol or (R)- or (S)-1-(9-anthryl)-2,2,2-trifluorethanol.
xe2x80x83Here also the bonding takes place via the oxygen atom.
(ix) According to a further embodiment, R3 can be derived from ephedrine, i.e. 2-methylamino-1-phenylpropan-1-ol. This compound is chiral and within the context of the present invention all stereoisomer forms must be included with this.
xe2x80x83The bonding of R3 again takes place via the oxygen atom, so that an ether structure results.
(x) Finally, R3 can also represent a phosphite radical of the general formula xe2x80x94P(OR10) (OR11), wherein R10 and R11 can be the same or different and represent an if necessary polycyclic or bridged aryl radical.
xe2x80x83Preferred examples are phosphate radicals with the formulas 
xe2x80x83Furthermore, R3 can represent:
(xi) C1-C10-alkyl, linear or branched,
(xii) acyl,
(xiii) benzyl or substituted benzyl radicals.
The substituent Y according to the general formula I represents Cl, Br, I, CN, COOH, COOR, CHO, CH2OR or C1-C10-alkyl.
In the group COOR or CH2OR the substituent R represents a linear or branched C1-C10-alkyl group or a substituted or unsubstituted aryl radical.
The substituent Y is selected so that it can be converted using simple, generally-known methods into a hydroxymethyl group. By way of example, an ester or carboxylic acid group is reduced directly, a halide can be converted via a Grignard intermediate stage into the corresponding carboxylic acid and then reduced, and a nitrile can first, for example, be hydrolysed to form the carboxylic acid and then reduced to a hydroxymethyl group.
Through this conversion of the substituent Y into a hydroxymethyl group, the 3,3-diphenylpropylamine derivatives described in WO 99/58478 can be produced in a simpler way. Suitable methods for converting the substituent Y into a hydroxymethyl group are also described there.
According to a preferred embodiment of the method according to the invention Y represents an ester group that is at paraposition to the substituent X.
Finally, the substituents R1 and R2, that can be the same or different, represent a C1-C10-alkyl group or a C3-C8-cycloalkyl group, wherein R1 and R2 can be linked to form a cyclical structure. This cyclical structure can contain heteroatoms, such as nitrogen, oxygen, etc., so that R1 and R2 together with the nitrogen atom, to which they are bonded, can, for example, form a morpholine radical.
According to a preferred embodiment of the method according to the invention, R1 and R2 represent isopropyl and AR represents phenyl.
Within the context of the present invention, the term xe2x80x9calkylxe2x80x9d means a linear or branched hydrocarbon chain with preferably between 1 and 10 C-atoms. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-Butyl and suitable isomers of pentyl and hexyl, wherein the isopropyl group is preferred.
The term xe2x80x9ccycloalkylxe2x80x9d or xe2x80x9ccycloalkyl groupxe2x80x9d describes cyclical hydrocarbon radicals with preferably between 3 and 10 carbon atoms, which can be substituted if necessary.
In the context of the present invention, substituents means groups known to a person skilled in the art such as alkyl, alkoxy, halogen (fluorine, chlorine, bromine, iodine), nitro and similar groups.
The term xe2x80x9csubstituted or unsubstituted benzylxe2x80x9d describes a benzyl group whose phenyl ring is substituted if necessary one or more times. Substituted benzyl groups are preferably 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-chlorobenzyl and 2-chlorobenzyl.
The term xe2x80x9calkylcarbonylxe2x80x9d describes groups of the formula Rxe2x80x94C(xe2x95x90O), wherein R represents an alkyl group. Preferred alkyl carbonyl groups are acetyl, proprionyl, isobutyryl, valeroyl and pivaloyl.
The term xe2x80x9ccycloalkylcarbonylxe2x80x9d describes a group of the formula Rxe2x80x94C(xe2x95x90O), wherein R represents a cycloalkyl group.
The term xe2x80x9carylxe2x80x9d designates an aromatic hydrocarbon radical such as phenyl (C6H5xe2x80x94), naphthyl (C10H7xe2x80x94) and anthryl (C14H9xe2x80x94). Phenyl and naphthyl groups are preferred, in particular phenyl groups, wherein these groups can be substituted one or more times. If necessary, two or more aryl radicals can be bridged or condensed with each other to form polycyclic structures.
The term xe2x80x9cbenzoylxe2x80x9d describes acyl groups of the formula xe2x80x94C(xe2x95x90O)xe2x80x94Ph, wherein the phenyl ring again can be substituted one or more times. Examples of such substituted acyl groups include 4-methoxybenzoyl, 2-methoxybenzoyl, 4-chlorobenzoyl, 2-chlorobenzoyl, 4-nitrobenzoyl and 2-nitrobenzoyl.
The term xe2x80x9calkoxycarbonylxe2x80x9d stands for Rxe2x80x94OC (xe2x95x90O) groups, wherein R represents an alkyl group. Preferred alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butyloxycarbonyl and benzyloxycarbonyl as well as alicyclic alkoxycarbonyl groups.
The term xe2x80x9camino acidxe2x80x9d or xe2x80x9camino acid radicalxe2x80x9d describes radicals that are derived from naturally occurring or synthetic amino acids (including all optical antipodes). Preferred amino acid radicals are valyl, leucyl, isoleucyl, phenylalanyl, prolyl, seryl, threonyl, methionyl and hydroxyprolyl.
The amino acid radical can be substituted by a suitable group. Examples of such substituted amino acid radicals are N-benzoylprolyl, N-tert.-butoxycarbonylprolyl, N-alkyl, N-acyl or N-diphenylphosphanylprolyl.
The method according to the invention is based on the hydrocarbonylation/hydroformylation of compounds of the general formula 
wherein X, Y and Ar are as defined above, and a subsequent reductive amination of the corresponding oxo-compounds. The oxo-compounds can be isolated or also converted in a xe2x80x9cone-stepxe2x80x9d reaction directly to the corresponding diarylamines. The method according to the invention therefore comprises the hydrocarbonylation/hydroformylation through synthesis gas, i.e. a mixture of carbon monoxide (CO) and hydrogen (H2) in the presence of suitable catalysts and the reductive amination with amines in the presence of suitable catalysts of the general formula HNR1R2, wherein R1 and R2 are as defined above. The hydroaminomethylation in the presence of primary amines leads to secondary amines while the conversion with secondary amine components leads to tertiary amines. In the method according to the invention, diisopropylamine is preferably used as an amine component.
According to a design example of the method according to the invention, the substituent X represents hydroxy (OH). This allows, starting with 1,1-diarylether compounds, the hydroformylation to chrome/lactol systems according to the general graphic formula shown below 
Liganden=ligands
These intermediate products are converted using known reactions into derivatives of the 2-[(3R)-3-(+)(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol, its acylated compounds and salts. Accurate descriptions of these reactions are contained in EP 0 957 073.
Procedural rules for reductive amination of compounds of the lactol type are also contained in WO 99/58478.
The abovementioned 1,1-diarylethene compounds according to general formula II can be produced using known methods as, for example, described in Yamaguchi M; Arisawa M; Omata K; Kabuto K; Hirama M; Uchimaru T; Journal of Organic Chemistry 1998, 63(21), 7298-7305 and Yamaguchi M; Hayashi A; Hirama M; Journal of the American Chemical Society 1995, 117(3), 1151-2.
The method according to the invention is generally conducted at a temperature in the range 50 to 200xc2x0 C. and preferably 100 to 140xc2x0 C.
The reaction pressure here is between 40 and 200 bar and preferably between 80 and 120 bar.
For the hydroformylation, a mixture of carbon monoxide and hydrogen (synthesis gas) is used, wherein the ratio of carbon monoxide (CO) to hydrogen (H2) is generally between 10/90 and 90/10 and preferably between 70/30 and 90/10.
The breadth of the pressure ratios is a result of the need to optimise the ratios between ligand and catalyst for each substrate separately and these are, therefore, dependent upon the substrate, catalyst preliminary stage and ligand, etc.
The reaction time is generally between 2 hours and 4 days and preferably in a range of between 1 and 3 days.
The abovementioned reaction times are influenced by the respective equipment set-up. With an optimum gas infeed, shorter reaction times can also be achieved.
The catalyst used in the method according to the invention includes one or more transition metals selected from the group comprising ruthenium, rhodium, platinum, cobalt, iridium, palladium and nickel, with preference being for rhodium.
According to a preferred embodiment of the method according to the invention, the catalyst is formed in-situ from a catalyst precursor and a ligand.
Suitable catalyst precursors are preferably [Rh(cod)Cl]2 and/or Rh(acac)(CO)2 or comparable rhodium complexes.
Suitable ligands are listed below along with the relevant abbreviation:
BINAPHOS=R-2-(diphenylphosphino)-1,1xe2x80x2-binaphthalen,-2xe2x80x2-yl-(S)-1,1xe2x80x2-binaphthalene-2,2xe2x80x2-diylphosphite,
DIOP=(2,2-dimethyl-4,5-diphenylphosphinomethyl)-1,3-dioxolane,
DIOP-DBP=(2,2-dimethyl-4,5-bis(5H-dibenzophosphol-5-ylmethyl)-1,3-dioxolane,
DPPB=1,4-bis(diphenylphosphino)butane,
CHIRAPHOS=2,3-bis(diphenylphosphino)butane,
CBDPP=1,2-bis(diphenylphosphinomethyl)cyclobutane,
CBDBP=1,2-bis(5H-dibenzophosphol-5-ylmethyl)cyclobutane,
CHDPP=1,2-bis(diphenylphosphinomethyl)cyclohexane,
CHDBP=1,2-bis(5H-dibenzophosphol-5-ylmethyl)cyclohexane,
CHDPPO=1,2-bis(diphenylphosphinoxy)cyclohexane,
BzMePhP*=benzyl-methyl-phenylphosphine,
CAMP=cyclohexyl-o-anisyl-methylphosphine,
NMDPP=neomenthyldiphenylphosphine,
PAMP=phenyl-o-anisyl-methylphosphine,
BPPM=(2S, 4S)-N-tert.butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine,
o-DPPB=ortho-diphenylphosphanylbenzoyl,
PBu3=tributylphosphine,
BINAP=2,2xe2x80x2-bis-(diphenylphosphino)-1,1xe2x80x2-binaphthyl. 
Phosphite and binaphthyl compounds can also be used as ligands.
Preferred ligands are tributylphosphine, (+)- or (xe2x88x92)-(2,2-dimethyl-4,5-diphenylphosphinomethyl)-1,3-dioxolane, (R)- or (S)-BINAP and/or (R,S)-BINAPHOS.
If tributylphosphine is used as a ligand, then the ratio of ligand to rhodium is generally between 1:1 and 25:1 and preferably between 4:1 and 10:1.
When (R)- or (S)-BINAP is used, it is between 1:1 and 6:1 and preferably between 1:1 and 2:1.
Finally, for (R, S)-BINAPHOS it is between 1:1 and 6:1 and preferably between 1:1 and 2:1.
The method according to the invention is based, as already stated above, on the hydroaminomethylation of 1,1-diarylethenes using a suitable catalyst system. It has the advantage that it can be conducted as a one step reaction, allowing the direct isolation of the desired diarylpropylamine derivative.
The chirality centre in position 3 of the 3,3-diarylpropylamine derivative can be generated by a suitable choice of chiral ligands for the metallic catalyst centre in a stereoselective fashion (ligand control). If one of the aryl groups in the 1,1-diarylethene used as the starting material is substituted in the ortho-position by a heteroatom, that is modified with chiral groups, the chiral synthesis is controlled by the substrate (substrate control). This is comparable with homoallylalcohols, the conformation of which is predetermined by the planar aromates. Finally, the combination of these methods (ligand and substrate control) allows double stereo side differentiation.
The method according to the invention is further explained using the following examples. In these, the following definitions apply:
TLC Thin Layer Chromatography
HPLC High Performance Liquid Chromatography
NMR Nuclear Magnetic Resonance
xc2x0 C. Degrees Celsius
RT Room Temperature
THF Tetrahydrofurane
acac Acetonylacetate
cod cis, cis-1,5-cyclooctadiene
abs. absolute
MTBE Methyl Tertiary Butyl Ether
h Hour(s)
TMS Tetra-Methyl-Silane
The NMR spectra are recorded using a DRX 400 from the Bruker company. TMS is used as an internal standard.
Mass spectres are measured on a Finnigan CA 5. The elemental composition is determined using a Leco CHNS-932.
Gas chromatographic investigations are carried out using a CarloErba GC-4160 with 25 m or with a Fisous GC-8130 with 30 m CP sil-5 capillaries.